Abstract

Genome-wide association studies have begun to uncover the complex genetic architecture of Alzheimer's disease (AD). Expression of many AD risk loci is enriched in microglia, the resident immune cells of the brain. Common variants near the MS4A gene family have been associated with AD risk and altered soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF). MS4A4A is a microglial gene that encodes a tetraspan membrane protein that regulates anti-inflammatory responses in macrophages. However, the mechanism by which MS4A4A contributes to microglial function and AD pathogenesis remains unknown. In this dissertation, I leveraged a novel mouse model to examine the impact of Ms4a4a deficiency on amyloid pathology and amyloid-mediated tau seeding and spread. In doing so, I discovered that loss of Ms4a4a shifts microglial states and contributes to AD pathology. Together, this work highlights the role of MS4A4A in microglial function and AD pathogenesis and suggests MS4A4A could serve as a therapeutic target, informing the development of more effective AD therapies.

Committee Chair

Celeste Karch

Committee Members

Aisling Chaney; David Holtzman; Erik Musiek; Joanna Jankowsky

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-1-2026

Language

English (en)

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